title: HIV-1 Tat-mediated induction of platelet-derived growth factor in astrocytes: role of early growth response gene 1.
abstract: HIV-associated neurologic disorders (HAND) are estimated to affect almost 60% of HIV-infected individuals. HIV encephalitis, the pathologic correlate of the most severe form of HAND, is often characterized by glial activation, cytokine-chemokine dysregulation, and neuronal damage and loss. However, the severity of HIV encephalitis correlates better with glial activation rather than viral load. Using the macaque model, it has been demonstrated that SIV encephalitis correlates with increased expression of the mitogen platelet-derived growth factor (PDGF) B chain in the brain. The goal of this study was to explore the role of PDGF-B chain in HIV-associated activation and proliferation of astrocytes. Specifically, the data demonstrate that exposure of rat and human astrocytes to the HIV-1 protein Tat resulted in the induction of PDGF at both the mRNA and protein levels. Furthermore, PDGF-BB induction was regulated by activation of ERK1/2 and JNK signaling pathways and the downstream transcription factor early growth response 1. Chromatin immunoprecipitation assays demonstrated binding of Egr-1 to the PDGF-B promoter. Exposure of astrocytes to PDGF-BB in turn led to increased proliferation and the release of proinflammatory cytokines MCP-1 and IL-1β. Because astrogliosis is linked to disease severity, understanding its regulation by PDGF-BB could aid in the development of therapeutic intervention strategies for HAND.
authors.affiliation: Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, KS 66160, USA.
authors.forename: Crystal
authors.initials: C
authors.lastname: Bethel-Brown
authors.forename: Honghong
authors.initials: H
authors.lastname: Yao
authors.forename: Shannon
authors.initials: S
authors.lastname: Callen
authors.forename: Young Han
authors.initials: YH
authors.lastname: Lee
authors.forename: Prasanta K
authors.initials: PK
authors.lastname: Dash
authors.forename: Anil
authors.initials: A
authors.lastname: Kumar
authors.forename: Shilpa
authors.initials: S
authors.lastname: Buch
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D000077214:Becaplermin; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D051766:Early Growth Response Protein 1 / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D015497:HIV-1 / Q000276:immunology; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism / Q000502:physiology; D010982:Platelet-Derived Growth Factor / Q000096:biosynthesis* / Q000235:genetics; D020574:Proto-Oncogene Proteins c-sis; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000502:physiology*
chemical_list: C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; C486110:Egr1 protein, rat; D018836:Inflammation Mediators; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D011994:Recombinant Proteins; D054322:tat Gene Products, Human Immunodeficiency Virus; D000077214:Becaplermin